Injection Device

ABSTRACT

The invention refers to an injection device comprising a housing ( 10; 410 ), a resilient member ( 90; 510 ) adapted to provide a force necessary for ejecting a dose from the injection device, and a dose setting member ( 80, 60 ) operatively connected to a dose indicator ( 120; 480 ) which is positioned within the housing ( 10; 410 ). The dose setting member ( 80, 60; 420, 440 ) and the dose indicator ( 120; 480 ) cooperate to set the dose to be ejected from the injection device. The dose indicator ( 120; 480 ), during dose setting, is adapted to undergo a mere rotational movement within the housing ( 10; 410 ) and relative to the housing ( 10; 410 ).

The present invention is generally directed to an injection device, i.e.a drug delivery device for selecting and dispensing a number of uservariable doses of a medicament.

Pen type drug delivery devices have application where regular injectionby persons without formal medical training occurs. This may beincreasingly common among patients having diabetes where self-treatmentenables such patients to conduct effective management of their disease.In practice, such a drug delivery device allows a user to individuallyselect and dispense a number of user variable doses of a medicament. Thepresent invention is not directed to so called fixed dose devices whichonly allow dispensing of a predefined dose without the possibility toincrease or decrease the set dose.

There are basically two types of drug delivery devices: resettabledevices (i.e., reusable) and non-resettable (i.e., disposable). Forexample, disposable pen delivery devices are supplied as self-containeddevices. Such self-contained devices do not have removable pre-filledcartridges. Rather, the pre-filled cartridges may not be removed andreplaced from these devices without destroying the device itself.Consequently, such disposable devices need not have a resettable dosesetting mechanism. The present invention is applicable for both types ofdevices, i.e. for disposable devices as well as for reusable devices.

A further differentiation of drug delivery device types refers to thedrive mechanism: There are devices which are manually driven, e.g. by auser applying a force to an injection button, devices which are drivenby a spring or the like and devices which combine these two concepts,i.e. spring assisted devices which still require a user to exert aninjection force. The spring-type devices involve springs which arepreloaded and springs which are loaded by the user during doseselecting. Some stored-energy devices use a combination of springpreload and additional energy provided by the user, for example duringdose setting.

These types of pen delivery devices (so named because they oftenresemble an enlarged fountain pen) are generally comprised of threeprimary elements: a cartridge section that includes a cartridge oftencontained within a housing or holder; a needle assembly connected to oneend of the cartridge section; and a dosing section connected to theother end of the cartridge section. A cartridge (often referred to as anampoule) typically includes a reservoir that is filled with a medication(e.g., insulin), a movable rubber type bung or stopper located at oneend of the cartridge reservoir, and a top having a pierceable rubberseal located at the other, often necked-down, end. A crimped annularmetal band is typically used to hold the rubber seal in place. While thecartridge housing may be typically made of plastic, cartridge reservoirshave historically been made of glass.

The needle assembly is typically a replaceable double-ended needleassembly. Before an injection, a replaceable double-ended needleassembly is attached to one end of the cartridge assembly, a dose isset, and then the set dose is administered. Such removable needleassemblies may be threaded onto, or pushed (i.e., snapped) onto thepierceable seal end of the cartridge assembly.

The dosing section or dose setting mechanism is typically the portion ofthe pen device that is used to set (select) a dose. During an injection,a spindle or piston rod contained within the dose setting mechanismpresses against the bung or stopper of the cartridge. This force causesthe medication contained within the cartridge to be injected through anattached needle assembly. After an injection, as generally recommendedby most drug delivery device and/or needle assembly manufacturers andsuppliers, the needle assembly is removed and discarded.

A disposable drug delivery device for selecting and dispensing a numberof user variable doses of a medicament according to the presentinvention typically comprises a housing, a cartridge holder forreceiving a cartridge, a lead screw or piston rod and means for drivingthe lead screw or piston rod during dose dispensing. Such a disposabledrug delivery device is known from WO 2004/078241 A1, wherein thecartridge holder is rigidly attached to the device housing. The pistonrod, which acts on a cartridge bung, is advanced by a driver during dosedispensing. The remaining dose in the cartridge is indicated to the userby the position of the bung and the distal end of the piston rod withinthe cartridge. Especially visually impaired users may find it difficultto identify the remaining dose in the cartridge.

EP 1 804 858 B1 discloses an injection device according to the preambleof claim 1. The device of EP 1 804 858 B1 comprises a housing, aresilient member and a dose setting member operatively connected to adose indicator barrel positioned within the housing. The resilientmember is a helical spring adapted to provide a force in the axialdirection of the injection device, the force being necessary forejecting a dose from the injection device. The dose setting member andthe dose indicator barrel are movable relative to each other andcooperate to set the dose to be ejected from the injection device. Thedose indicator barrel engages a threaded portion of the housing. Thedose indicator barrel, during dose setting, is adapted undergo acombined rotational and translational movement within the housing andrelative to the housing. The combined rotational and translationalmovement of the dose indicator barrel is caused by its threadedinterface with the housing. Generally, a translational movement of adose indicator barrel during dose setting either results in theindicator barrel protruding from the housing depending on the amount ofthe set dose or this requires a relatively long housing, if it ispreferred that the barrel is covered within the housing independent ofthe set dose.

Further, WO 2008/145171 A1 describes an injection device where the forcenecessary for ejecting a dose from the injection device is establishedmanually, i.e. without the aid of a spring or the like. This devicecomprises a housing, a first component for pressing out the injectionliquid from a container and a dosing component in threaded engagementwith the first component. The dosing component can rotate together withthe first component relative to the housing for the purpose of selectinga desired injection dosing. Further, the dosing component is in threadedengagement with a window sleeve which moves axially within the housingand relative to the dosing component upon rotation of the dosingcomponent. A number scale provided on the dosing component is visiblethrough this window sleeve. A knob is provided, which is rotated duringdose setting and which is simultaneously axially moved away from thehousing as the window sleeve translates out of the housing during dosesetting. Thus, although the dosing component does not perform atranslational movement during dose setting, there is still a component(knob with window sleeve) protruding from the housing when a dose isset. A similar manually operated device is known from WO 2010/020311 A1,wherein the window sleeve is not limpid but has a structure distortingthe view on the dosing component. A window in the housing has acorresponding distorting structure which may partially reverse thedistorting effect of the window sleeve. This device comprises a limitermechanism defining a maximum settable dose and/or a minimum settabledose provided by axial abutment of protrusions on the window sleeve andthe boundaries of a housing aperture.

Further manually driven devices requiring the user to apply a force toan injection button to expel a dose are known from WO 2012/049139 A1, WO2012/049138 A1 and US 2009/264828 A1.

A drawback of these known devices is that the force necessary forejecting a dose from the injection device has to be provided by the userduring dose administration which may cause difficulties e.g. for userswith impaired dexterity.

It is an object of the present invention to provide a drug deliverydevice requiring low dispensing forces applied by the user and animproved indication of the set dose. It is a further object to make thedrug delivery device compact in size, preferably without componentstranslating out of the housing during dose setting.

This object is solved by a device as defined in claim 1.

According to a first embodiment of the present invention the injectiondevice comprises a housing, a resilient member adapted to provide aforce necessary for ejecting a dose from the injection device, and adose setting member operatively connected to a dose indicator. The dosesetting member is positioned within the housing. The dose setting memberand the dose indicator cooperate to set the dose to be ejected from theinjection device. The dose indicator, during dose setting, is adapted toundergo a mere rotational movement within the housing and relative tothe housing. This dose indicator may be rotatable for severalrevolutions, i.e. for more than 360°. In other words, the dose indicatordoes not perform a translational movement during dose setting. Thisprevents that the dose indicator is wound out of the housing or that thehousing has to be prolonged for covering the dose indicator within thehousing. It is preferred if the device is suitable for dispensingvariable, user-selectable, doses of medicament. The device may be adisposable device, i.e. a device which does not provide for an exchangeof an empty cartridge.

Preferably, the injection device further comprises a piston rod having athreaded outer surface with at least one drive track arranged in alongitudinal direction of the outer surface of the piston rod. Inaddition, the injection device may comprise a drive member engaging atleast part of the drive track of the piston rod and being releasablycoupled to the dose indicator. The drive member may be adapted to driveand rotate with the piston rod during ejection of a dose from theinjection device. If the housing has a threaded portion cooperating withthe threaded outer surface of the piston rod, rotation of the piston rodmay result in axial movement of the piston rod.

According to a further embodiment of the present invention, theinjection device further comprises a gauge element which is rotationallyconstrained to the housing and axially displaceable relative to thehousing. The position of the gauge element may thus be used to identifythe actually set and/or dispensed dose. Different colours of sections ofthe gauge member may facilitate identifying the set and/or dispenseddose without reading numbers, symbols or the like on a display.

Preferably, the gauge element is in threaded engagement with the doseindicator such that rotation of the dose indicator causes an axialdisplacement of the gauge element relative to the dose indicator andrelative to the housing. The gauge element may have the form of a shieldor strip extending in the longitudinal direction of the device. As analternative, the gauge element may be a sleeve.

In an embodiment of the invention, the dose indicator is marked with asequence of numbers or symbols and the gauge element comprises anaperture or window. With the dose indicator located radially inwards ofthe gauge element, this allows that at least one of the numbers orsymbols on the dose indicator is visible through the aperture or window.In other words, the gauge element may be used to shield or cover aportion of the dose indicator and to allow view only on a limitedportion of the dose indicator. This function may be in addition to thegauge element itself being suitable for identifying or indicating theactually set and/or dispensed dose.

The resilient member is preferably a torsion spring. Such a torsionspring may be strained during dose setting. The spring is preferablypreloaded and is further strained by the user during dose setting. Thestored energy is at least in part released during dose dispensing.

According to a preferred embodiment, the drug delivery device comprisesa limiter mechanism defining a maximum settable dose and a minimumsettable dose. Typically, the minimum settable dose is zero (0 IU ofinsulin formulation), such that the limiter stops the device at the endof dose dispensing. The maximum settable dose, for example 60, 80 or 120IU of insulin formulation, may be limited to avoid overdosage.Preferably, the limits for the minimum dose and the maximum dose areprovided by hard stop features.

The limiter mechanism may comprise a first rotational stop on the doseindicator and a first counter stop on the gauge element, which abut inthe minimum dose (zero) position, and a second rotational stop on thedose indicator and a second counter stop on the gauge element, whichabut in the maximum dose position. As the dose indicator rotatesrelative to the gauge element during dose setting and during dosedispensing, these two components are suitable to form a reliable androbust limiter mechanism.

To prevent an underdosage or a malfunction, the drug delivery device maycomprise a last dose protection mechanism for preventing the setting ofa dose, which exceeds the amount of liquid left in a cartridge. In apreferred embodiment, this last dose protection mechanism only detectsthe medicament remaining in the cartridge when the cartridge containsless than the maximum dose (e.g. 120 IU).

For example, the last dose protection mechanism comprises a nut memberlocated interposed between the drive member and a component whichrotates during dose setting and dose dispensing. The component whichrotates during dose setting and dose dispensing may be the doseindicator or a dial sleeve rotationally constrained to the doseindicator. In a preferred embodiment, the dose indicator and/or a dialsleeve rotate during dose setting and during dose dispensing, whereasthe drive member only rotates during dose dispensing together with thedose indicator and/or the dial sleeve. Thus, in this embodiment, the nutmember will only move during dose setting and will remain stationarywith respect to these components during dose dispensing. Preferably, thenut member is threaded to the drive member and splined to the doseindicator and/or the dial sleeve. As an alternative, the nut member maybe threaded to the dose indicator and/or the dial sleeve and may besplined to the drive member. The nut member may be a full nut or a partthereof, e.g. a half nut.

The sequence of dose setting and dose dispensing usually requires arelative movement of some of the components either during dose settingand/or during dose dispensing. Various different embodiments ofachieving this result are possible, some of which are described in theprior art mentioned above. According to a preferred example of theinvention, the injection device may further comprise a clutch arrangedbetween the drive member and the dose indicator, wherein the clutchallows relative rotation of the drive member and the dose indicatorduring dose setting and rotationally constrains the drive member and thedose indicator during dose dispensing. Alternative embodiments mayinclude a relative axial movement during dose setting or a jointmovement during dose setting followed by a relative movement during dosedispensing.

The injection device may comprise at least one clicker mechanism forgenerating a tactile and/or audible feedback. Preferably, the clickermechanism signifies the end of dose dispensing. In a preferredembodiment of the invention, the device comprises at least a firstclicker producing an audible and/or tactile first feedback during dosesetting and/or dose dispensing and a second clicker producing an audibleand/or tactile second feedback, distinct from the first feedback, duringdose dispensing when the device reaches its minimum dose (zero)position. The injection device may have different clickers active duringdose setting and during dose dispensing.

Spring loaded injection devices often comprise an actuation element forreleasing the energy stored in the resilient member, e.g. in the spring.Typically, the user presses or activates this actuating element after adose has been set to initiate dose dispensing. According to a firstembodiment, the actuating element may comprise a button located at theproximal end of the housing, i.e. the end facing away from the needle.As an alternative, a trigger may be provided located on a lateral sideof the housing, preferably in the distal region of the device. Theactuation element may act on the clutch to rotationally constrain thedrive member and the dose indicator for dose dispensing.

The drug delivery device may comprise a cartridge containing amedicament. The term “medicament”, as used herein, means apharmaceutical formulation containing at least one pharmaceuticallyactive compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antihousing or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exendin-3 or exendin-4 or an analogue or derivative ofexendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoylLysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoylThrB29LysB30human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-GlyGlu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,des Pro36 Exendin-4(1-39), des Pro36 [Asp28] Exendin-4(1-39),des Pro36 [IsoAsp28] Exendin-4(1-39), des Pro36 [Met(O)14, Asp28]Exendin-4(1-39), des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); ordes Pro36 [Asp28] Exendin-4(1-39), des Pro36 [IsoAsp28] Exendin-4(1-39),des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),

wherein the group -Lys6-NH2 may be bound to the C-terminus of theExendin-4 derivative;

or an Exendin-4 derivative of the sequence

des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010), H-(Lys)6-des Pro36 [Asp28]Exendin-4(1-39)- Lys6-NH2, des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin- 4(1-39)-NH2,H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,des Pro36, Pro37, Pro38 [Asp28] Exendin- 4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin- 4(1-39)-Lys6-NH2,H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25,  Asp28]Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25,  Asp28]Exendin-4(1-39)-(Lys)6-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25,  Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Met(O)14, Asp28]Exendin- 4(1-39)-Lys6-NH2, des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2, H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14,  Asp28]Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2, des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28 Exendin-4(1-39)-(Lys)6-NH2,H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14,  Trp(O2)25]Exendin-4(1-39)-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14,  Asp28]Exendin-4(1-39)-NH2, H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25,   Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14,  Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2;

or a pharmaceutically acceptable salt or solvate of any one of theafore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antihousing is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype ofantihousing; these chains are found in IgA, IgD, IgE, IgG, and IgMantibodies, respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and δ approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (CH) and the variable region (VH). In onespecies, the constant region is essentially identical in all antibodiesof the same isotype, but differs in antibodies of different isotypes.Heavy chains γ, α and δ have a constant region composed of three tandemIg domains, and a hinge region for added flexibility; heavy chains μ andε have a constant region composed of four immunoglobulin domains. Thevariable region of the heavy chain differs in antibodies produced bydifferent B cells, but is the same for all antibodies produced by asingle B cell or B cell clone. The variable region of each heavy chainis approximately 110 amino acids long and is composed of a single Igdomain.

In mammals, there are two types of immunoglobulin light chain denoted byλ and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antihousing contains two lightchains that are always identical; only one type of light chain, κ or λ,is present per antihousing in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antihousing is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antihousing fragment” contains at least one antigen binding fragmentas defined above, and exhibits essentially the same function andspecificity as the complete antihousing of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H—H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

Non-limiting, exemplary embodiments of the invention will now bedescribed with reference to the accompanying drawings, in which:

FIG. 1 shows an exploded view of the components of an injection devicein accordance with a first embodiment of the present invention;

FIG. 2 shows a perspective view of the device of FIG. 1;

FIG. 3 shows a sectional view of the device of FIG. 1;

FIG. 4 shows an enlarged view of a detail of the device of FIG. 1;

FIG. 5 shows an enlarged view of a detail of the device of FIG. 1;

FIG. 6 shows an enlarged sectional view of a detail of the device ofFIG. 1;

FIG. 7 shows a sectional view of the device of FIG. 1 in the at reststate;

FIG. 8 shows a sectional view of the device of FIG. 1 in the activatedstate;

FIG. 9 shows an enlarged sectional view of a detail of the device ofFIG. 1;

FIG. 10 shows an exploded view of the components of an injection devicein accordance with a second embodiment of the present invention;

FIG. 11 shows a perspective view of the device of FIG. 10;

FIG. 12 shows a sectional view of the device of FIG. 10;

FIG. 13 shows an enlarged view of a detail of the device of FIG. 10;

FIG. 14 shows an enlarged sectional view of a detail of the device ofFIG. 10;

FIGS. 15 a, b show an enlarged view of a detail of the device of FIG.10;

FIGS. 16 a, b show an enlarged view of a detail of the device of FIG.10;

FIG. 17 shows a sectional view of the device of FIG. 10 in the at reststate;

FIG. 18 shows a sectional view of the device of FIG. 10 in the activatedstate

FIG. 19 shows a sectional view of an injection device in accordance witha third embodiment of the present invention in the at rest state;

FIG. 20 shows a sectional view of the device of FIG. 19 in the activatedstate;

FIG. 21 shows an exploded view of the components of an injection devicein accordance with a fourth embodiment of the present invention; and

FIG. 22 shows a partially cut away side view of the device of FIG. 21.

FIG. 2 shows a drug delivery device in the form of an injection pen. Thedevice has a distal end (upper end in FIG. 2) and a proximal end (lowerend in FIG. 2). The component parts of the drug delivery device areshown in FIG. 1. The drug delivery device comprises a housing 10, acartridge holder 20, a lead screw (piston rod) 30, a driver 40, a nut50, a dial sleeve 60, a button 70, a dose selector 80, a torsion spring90, a locking arm 100, a gauge element 110, a dose indicator (numbersleeve) 120, a clutch plate 130, a clutch spring 140, a return spring150, a bearing 160 and a cartridge 170. A needle arrangement (not shown)with a needle hub and a needle cover may be provided as additionalcomponents, which can be exchanged as explained above.

The housing 10 or body is a generally tubular element. In the embodimentshown in the figures, the housing 10 provides location for the liquidmedication cartridge 170 and cartridge holder 20, an interface torotationally constrain the locking arm 100, a slot 11 or lens throughwhich the dose number on the dose indicator 120 can be viewed, and afeature, e.g. a circumferential groove, on its external surface toaxially retain the dose selector 80. A flange-like inner wall 12comprises an inner thread engaging the piston rod 30. Further a clickerarm 13 or beam is integrated into the housing 10 for interaction withthe driver 40.

The cartridge holder 20 is located at the distal side of housing 10. Thecartridge holder may be a transparent or translucent component which istubular to receive cartridge 170. The distal end (upper end in FIG. 2)of cartridge holder 20 may be provided with means for attaching a needlearrangement. A removable cap (not shown) may be provided to fit over thecartridge holder 20 and may be retained via clip features.

The lead screw 30 is an elongate member with an outer thread 31 which isrotationally constrained to the driver 40 via a splined interface. Theinterface comprises at least one longitudinal groove or track 32 and acorresponding protrusion or spline 44 of the driver 40. When rotated,the lead screw 30 is forced to move axially relative to the driver 40,through its threaded interface with the housing 10.

The driver 40 is a sleeve which extends from the interface with the dialsleeve 60 via the clutch plate 130 down to a splined tooth interface 41with the locking arm 100. This provides rotational constraint of thelocking arm 100 to the driver 40 during dose setting. When the dosebutton 70 is pressed, these spline teeth are disengaged allowing thedriver 40 to rotate. Further, teeth 42 are provided at the proximal endface of driver 40 for engagement with clutch plate 130. The driver 40has a threaded section 43 providing a helical track for the nut 50. Inaddition, a last dose abutment is provided which may be the end of thethread 43 track or preferably a rotational hard stop limiting movementof the nut 50 on the thread 43.

The nut 50 is part of a last dose limiter mechanism. The nut 50 islocated between the dial sleeve 60 and the driver 40. It is rotationallyconstrained to the dial sleeve 60, via a splined interface. It movesalong a helical path relative to the driver 40, via a threadedinterface, when relative rotation occurs between the dial sleeve 60 anddriver 40 during dialling. As an alternative, the nut 50 may be splinedto the driver 40 and threaded to the dial sleeve 60. In the embodimentof FIGS. 1 to 9, the nut 50 is a half nut, i.e. a component extendingapproximately 180° around the center axis of the device. As analternative, if the driver 40 was formed from two separate componentsthat became rigidly engaged during assembly then the nut 50 could alsobe a complete nut.

The dial sleeve 60 is a tubular element. It receives the clutch plate130 and the proximal end of the driver 40 to which it may be coupled viathe clutch plate. The distal end of the dial sleeve 60 is permanentlyconstrained to the dose indicator 120. For manufacturing reasons, thedial sleeve 60 and the dose indicator 120 are separate components.However, they could be integrated into a single component part.

The button 70 forms the proximal end of the device. Button 70 has anannular skirt 71 received within dose selector 80. Further, button 70has a proximal end plate onto which a button cover may be placed asindicated in FIG. 1. The dose button 70 is permanently splined to thedose selector 80 and splined to the dial sleeve 60 by respective splinefeatures 71, 72 when the button 70 is not pressed. This spline interface71, 72 is disconnected when the dose button 70 is pressed. Dosedispensing is initiated by actuation of dose button 70. FIG. 6 shows thespline features 72 as teeth and spline features 71 may be designed in asimilar manner such that these teeth 71, 72 are allowed to engage ordisengage corresponding teeth on the inner surface of dose selector 80and the outer surface of dose dial sleeve 60, respectively.

The dose selector 80 or dose dial grip is a sleeve-like component with aserrated outer skirt. The dose selector 80 is axially constrained to thehousing 10. It is rotationally constrained, via the splined interface,to the dose button 70. This splined interface remains engagedirrespective of the dose button 70 axial position.

The torsion spring 90 is attached at one end to the housing 10 and atthe other end to the dose indicator 120. The torsion spring 90 ispre-wound upon assembly, such that it applies a torque to the doseindicator 120 when the mechanism is at zero units dialled. The action ofrotating the dose selector 80, to set a dose, rotates the dose indicator120 relative to the housing 10, and charges the torsion spring 90. Thetorsion spring 90 is located inside the dose indicator 120 and surroundsa distal portion of the driver 40.

The locking arm 100 is rotationally fixed to the housing 10 but allowedto translate axially. Axial movement is effected by the dose button 70which abuts with its distal face the proximal face of the locking arm100. Near its distal end, the locking arm 100 has teeth 101 forreleasably coupling the tooth interface 41 of driver 40 to the housing10 via the locking arm 100.

The gauge element 110 is a window element which is constrained toprevent rotation but allow translation relative to the housing 10 via asplined interface. It is also in threaded engagement to the doseindicator 120 such that rotation of the dose indicator 120 causes axialtranslation of the gauge element 110. The gauge element 110 has helicalcuts in its inner surface which provide clearance for stop features onthe dose indicator 120 as the gauge element 110 traverses axially duringnumber sleeve rotation. The gauge element 110 is positioned in housing10 such that it is guided within slot 11 and closes same. It is agenerally plate or band like component having a central aperture 111 orwindow and two flanges 112, 113 extending on either side of theaperture. The flanges 112, 113 are preferably not transparent and thusshield or cover the dose indicator 120, whereas the aperture 111 orwindow allows viewing a portion of the number sleeve. Further, gaugeelement 110 has an arm 114 interacting with the dose indicator 120 atthe end of dose dispensing. The gauge element 110 is shown in moredetail in FIG. 5 together with dose indicator 120.

The dose indicator 120 is a number sleeve which is rotationallyconstrained, via a splined interface, to the dial sleeve 60. They areconstrained to the housing 10 to allow rotation but not translation. Thedose indicator 120 is marked with a sequence of numbers, which arevisible through the central aperture 111 in the gauge element 110 and aslot 11 in the housing 10, to denote the dialled dose of medicament. Alock ring 121 may be rigidly constrained to the dose indicator 120. Thisring is only a separate component to simplify the number sleeve mouldtooling. The dose indicator 120 has a ramp-like rotational stop 122abutting against a lateral side of the gauge element 110 in a position,where a dose of zero units is dialled (minimum dose position). A similarstop is provided on the opposite side of the dose indicator 120 toprevent setting of a dose above the maximum dose, e.g. above 120 units.A flexible arm 123 is provided interacting with the arm 114 of the gaugeelement 110 at the end of dose dispensing.

The clutch plate 130 is splined to the dial sleeve 60. It is alsocoupled to the driver 40 via a ratchet interface 42, 131, which occurson an axial abutment. The ratchet 42, 131 provides a detented positionbetween the dial sleeve 60 and driver 40 corresponding to each doseunit, and engages different ramped tooth angles during clockwise andanti-clockwise relative rotation. FIG. 6 shows the clutch plate 130together with the proximal end of the device in more detail.

The clutch spring 140 is located interposed between button 70 and clutchplate 130. It acts on the clutch plate allowing the ratchet teeth 42,131 to bump over each other during dose setting against the axial forceof the spring.

The return spring 150 acts against the locking arm 100 to force thespline teeth 101 into engagement with the teeth 41 of driver 40.

The bearing 160 is axially constrained to the lead screw 30 and acts onthe bung within the liquid medicament cartridge 170.

The cartridge 170 is received in cartridge holder 20. The cartridge 170may be a glass ampule having a moveable rubber bung 171 at its proximalend. The distal end of cartridge 170 is provided with a pierceablerubber seal which is held in place by a crimped annular metal band. Inthe embodiment depicted in the figures, the cartridge 170 is a standard1.5 ml cartridge. The device is designed to be disposable in that thecartridge 170 cannot be replaced by the user or health careprofessional. However, a reusable variant of the device could beprovided by making the cartridge holder 20 removable and allowingbackwinding of the lead screw 30 and the resetting of nut 50.

The axial position of the locking arm 100, clutch plate 130 and dosebutton 70 is defined by the action of the return spring 150 and clutchspring 140, which apply a force on the locking arm 100 and dose button70 in the proximal direction. In the “at rest” position (shown in FIG.2), this ensures that the dose button 70 splines are engaged with thedial sleeve 60 and that the driver 40 teeth 41 are engaged with thelocking arm 100.

In the following, the functioning of the disposable drug delivery deviceand its components will be explained in more detail.

When the device is at rest as shown in FIG. 2, the dose indicator 120 ispositioned against its zero dose abutment (FIG. 4) with the gaugeelement 110 and the dose button 70 is not depressed. Dose marking ‘0’ onthe dose indicator 120 is visible through the window of the housing 10and the central aperture 111 in the gauge element 110. The torsionspring 90, which has a number of pre-wound turns applied to it duringassembly of the device, applies a torque to the dose indicator 120 andis prevented from rotating by the zero dose abutment 122. It might alsobe possible to “back-wind” the mechanism slightly due to an offsetbetween the zero dose stop 122 and the angular offset of the driver 40spline teeth 41. This has the effect of preventing possible weepage whena dose is dialled and the zero dose abutment is disengaged.

The user selects a variable dose of liquid medicament by rotating thedose selector 80 clockwise, which generates an identical rotation in thedial sleeve 60 and hence dose indicator 120. Rotation of the doseindicator 120 causes charging of the torsion spring 90, increasing theenergy stored within it. As the dose indicator 120 rotates, the gaugeelement 110 translates axially due to its threaded engagement therebyshowing the value of the dialled dose. As mentioned above, the gaugeelement 110 has flanges 112, 113 either side of the central aperture 111which may have visual differentiation to provide additional feedback tothe dialled/delivered dose value. The embodiment of FIGS. 1 to 9utilises a dose selector 80 with an increased diameter relative to thehousing 10 which aids dialling. The driver 40 is prevented fromrotating, due to the engagement of its splined teeth 41 with the lockingarm 100. Relative rotation must therefore occur between the clutch plate130 and driver 40 via the ratchet interface 42, 131.

The user torque required to rotate the dose selector 80 is a sum of thetorque required winding up the torsion spring 90, and the torquerequired overhauling the ratchet feature 42, 131. The clutch spring 140is designed to provide an axial force to the ratchet feature and to biasthe clutch plate 130 onto the driver 40. This axial load acts tomaintain the ratchet teeth engagement of the clutch plate 130 and driver40. The torque required to overhaul the ratchet 42, 131 is resultantfrom the axial load applied by the clutch spring 140, the clockwise rampangle of the ratchet 42, 131, the friction coefficient between themating surfaces and the mean radius of the ratchet features.

As the user rotates the dose selector 80 sufficiently to increment themechanism by 1 unit, the dial sleeve 60 rotates relative to the driver40 by 1 ratchet tooth. At this point the ratchet teeth 42, 131 re-engageinto the next detented position. An audible click is generated by theratchet re-engagement, and tactile feedback is given by the change intorque input required.

Relative rotation of the dial sleeve 60 and the driver 40 also causesthe nut 50 to travel along its threaded path, towards its last doseabutment on the driver 40.

With no user torque applied to the dose selector 80, the dial sleeve 60is now prevented from rotating due to the action of the torque appliedby the torsion spring 90, solely by the ratchet 42, 131 engagementbetween the clutch plate 130 and the driver 40. The torque necessary tooverhaul the ratchet 42, 131 in the anti-clockwise direction isresultant from the axial load applied by the clutch spring 90, theanti-clockwise ramp angle of the ratchet, the friction coefficientbetween the mating surfaces and the mean radius of the ratchet features.The torque necessary to overhaul the ratchet 42, 131 must be greaterthan the torque applied to the dial sleeve 60 and hence clutch plate 130by the torsion spring 90. The ratchet ramp angle is therefore increasedin the anti-clockwise direction to ensure this is the case whilstensuring the dial-up torque is as low as possible.

The user may now choose to increase the selected dose by continuing torotate the dose selector 80 in the clockwise direction. The process ofoverhauling the ratchet interfaces between the dial sleeve 60 and driver40 is repeated for each dose unit. Additional energy is stored withinthe torsion spring 90 for each dose unit and audible and tactilefeedback is provided for each unit dialled by the re-engagement of theratchet teeth 42, 131. The torque required to rotate the dose selector80 increases as the torque required to wind up the torsion spring 90increases. The torque required to overhaul the ratchet 42, 131 in theanti-clockwise direction must therefore be greater than the torqueapplied to the dial sleeve 60 by the torsion spring 90 when the maximumdose has been reached.

If the user continues to increase the selected dose until the maximumdose limit is reached, the dose indicator 120 engages with its maximumdose abutment on the gauge element 110. This prevents further rotationof the dose indicator 120, dial sleeve 60, clutch plate 130 and doseselector 80. Depending on how many units have already been delivered bythe mechanism, during selection of a dose, the nut 50 may contact itslast dose abutment with the driver 40. The abutment prevents furtherrelative rotation of the dial sleeve 60 and the driver 40, and thereforelimits the dose that can be selected. The position of the nut 50 isdetermined by the total number of relative rotations between the dialsleeve 60 and driver 40, which have occurred each time the user sets adose.

With the mechanism in a state in which a dose has been selected, theuser is able to deselect any number of units from this dose. Deselectinga dose is achieved by the user rotating the dose selector 80anti-clockwise. The torque applied to the dose selector 80 by the useris sufficient, when combined with the torque applied by the torsionspring 90, to overhaul the ratchet 42, 131 between the clutch plate 130and driver 40 in the anti-clockwise direction. When the ratchet isoverhauled, anti-clockwise rotation occurs in the dial sleeve 60 via theclutch plate 130, which returns the dose indicator 120 towards the zerodose position, and unwinds the torsion spring 90. The relative rotationbetween the dial sleeve 60 and driver 40 causes the nut 50 to returnalong its helical path (thread 43), away from the last dose abutment onthe driver 40.

With the mechanism in a state in which a dose has been selected, theuser is able to activate the mechanism to commence delivery of a dose.Delivery of a dose is initiated by the user depressing the dose button70 at the proximal end of the device. FIGS. 7 and 8 show the device inthe two positions dose button 70 in at rest condition (FIG. 7) and dosebutton 70 depressed (FIG. 8). When the dose button 70 is depressed,splines 71, 72 to the dial sleeve 60 and the dose button 70 aredisengaged, rotationally disconnecting the dose selector 80 from thedelivery mechanism so that the dose selector 80 does not rotate duringdispense. The dose button 70 acts on the locking arm 100, which travelsaxially disconnecting the splined tooth engagement 41, 101 to the driver40. The driver 40 can now rotate and is driven by the torsion spring 90via the dose indicator 120, dial sleeve 60 and clutch plate 130.Rotation of the driver 40 causes the lead screw 30 to rotate due totheir splined engagement, and the lead screw 30 then advances due to itsthreaded engagement to the housing 10. The number sleeve rotation alsocauses the gauge element 110 to traverse axially back to its zeroposition whereby the zero dose abutment 122 stops the mechanism.

Tactile feedback during delivery is provided via a compliant cantileverbeam 13 integrated into the housing 10, which interfaces axially withthe spline teeth 41 of the driver 40, whereby the spline teeth spacingcorresponds to the driver 40 rotation required for a single unitdispense. During dispense, as the driver 40 rotates, the spline features41 engage with the clicker arm 13 to produce an audible click with eachdose unit delivered. Delivery of a dose continues via the mechanicalinteractions described above while the user continues to depress thedose button 70.

If the user releases the dose button 70, the clutch spring 140 and thereturn spring 150 co-operate to return the dose button to its at restposition. The return spring 150 acts on the dose button 70 via thelocking arm 100 so this is also translated axially. As the locking arm100 returns towards its at rest position the splines 101 engage with thespline features 41 of the driver 40, rotationally constraining thedriver 40 relative to the housing 10 and halting the delivery of thedose.

During delivery of a dose, the driver 40 and dial sleeve 60 rotatetogether, so that no relative motion in the nut 50 occurs. The nut 50therefore travels towards its abutment on the driver 40 during diallingonly.

Once the delivery of a dose is stopped, by the dose indicator 120returning to the zero dose abutment, the user may release the dosebutton 70, which will re-engage the locking arm 100 spline teeth withthe driver 40. The mechanism is now returned to the at rest condition.

It is possible to angle the spline teeth 41, 101 on either one or bothof the driver 40 and locking arm 100 so that when the dose button 70 isreleased the re-engagement of the spline teeth fractionally ‘backwinds’the driver 40 thereby removing the engagement of the dose indicator 120to the gauge element 110 zero dose stop abutment 122. This removes theeffect of clearances in the mechanism (for example due to tolerances)which could otherwise lead to slight advancement of the lead screw 30and medicament dispense when the device is dialled for the subsequentdose (due to the dose indicator 120 zero dose stop 122 no longerrestraining the mechanism and instead the restraint returning to thesplines between the drive sleeve and locking arm 100.

At the end of dose, additional audible and/or tactile feedback isprovided in the form of a click, distinct from the clicks providedduring dispense, to inform the user that the device has returned to itszero position. This is achieved by the interaction of three components,namely the dose indicator 120, the gauge element 110 and the locking arm100. This embodiment allows feedback to only be created at the end ofdose delivery and not created if the device is dialled back to, or awayfrom, the zero position. FIG. 4 shows the position of the features whena dose is dialled. It can be seen that the locking arm 100 does notcontact the flexible arm 123 of the dose indicator 120 and thereforeduring dialling the flexible arm 123 is not deflected. However, duringdose delivery, the locking arm 100 is in an axially advanced (distal)position whereby it deflects the flexible arm 123 of the number sleeveaxially. As can be seen in FIG. 4, the locking arm 100 has a cut out orslot having a distal face 102, which interacts with a protrusion 124 onthe arm 123 if the locking arm 100 is displaced in the distal directionupon depression of button 70. Thus, the flexible arm 123 on the doseindicator 120 is deflected axially by locking arm 100 only when the dosebutton 70 is depressed, i.e. during dose dispensing and not during dosesetting or dose cancelling. As the dose indicator 120 returns to itszero position, the flexible arm 123 contacts with a further protrusion125 the semi-flexible arm 114 of the gauge element 110. At the zeroposition, the flexible arm 123 over-rides the arm 114 of the gaugeelement 110 creating a distinctive click feedback. In the embodiment ofFIG. 4, arm 114 has a recess 115 into which the protrusion 125 snaps toincrease the audible and/or tactile feedback at the zero position.

A second embodiment is depicted in FIGS. 10 to 18. The general functionof this device is similar to that of the first embodiment. Thus,identical or highly similar components are marked with the samereference numerals as with the first embodiment. As can be taken fromthe overview of the component parts in FIG. 10, this embodiment has atrigger 200 for displacing driver 40 by means of an internal actuationelement, which is referred to as the trigger inner 210. The trigger 200is pivotably held on the housing 10 by means of a trigger housing 220.In addition, an inner housing 190 and a grip cover 180 are provided. Allcomponents, except for the trigger 200 and the trigger housing 220, arelocated concentrically about a common principal axis of the mechanism.

The housing 10 provides location for the liquid medication cartridge170, the mount points for the trigger housing 220, an interface torigidly constrain the inner housing 190, a slot 11 through which thedose number on the dose indicator 120 can be viewed, and a feature, e.g.a circumferential groove, on its external surface to axially retain thedose selector 80.

A removable cap (not shown) may be provided to fit over the cartridgeholder 20 of the housing 10 and may be retained onto the housing 10 viaclips when the mechanism is not in use. When the cap is fitted onto thehousing 10, a mechanical interlock may be created with the trigger 200,which prevents the trigger 200 from being depressed from its at restposition.

The lead screw 30 has an outer thread 31 and is rotationally constrainedto the driver 40 via a splined interface. The interface comprises atleast one longitudinal groove or track 32 and a corresponding protrusionor spline 44 of the driver 40. Similar to the first embodiment, whenrotated, the lead screw 30 is forced to move axially relative to thedriver 40, through a threaded interface with the housing 10.

The driver 40 extends from the interface with the dial sleeve 60 via theclutch plate 130 down to a splined tooth interface 41, 191 with theinner housing 190, which occurs on an axial abutment. This providesrotational constraint for the driver 40 during dose setting. As in thefirst embodiment, an end stop for the nut 50 is provided (not shown).

The nut 50 is located between the dial sleeve 60 and the driver 40. Itis rotationally constrained to the dial sleeve 60, via a splinedinterface. It moves along a helical path relative to the driver 40, viaa threaded interface, when relative rotation occurs between the dialsleeve 60 and driver 40. Again, the engagement of the nut 50 with thedriver 40 and the dial sleeve 60 may be vice versa. Thus nut 50 isdepicted as a half nut, but may have the form of a full nut.

The dial sleeve 60 is coupled to the driver 40 via a ratchet interfaceon the clutch plate 130, which occurs on an axial abutment. The ratchetwhich is formed by teeth 42, 131 provides a detented position betweenthe dial sleeve 60 and driver 40 corresponding to each dose unit, andengages different ramped tooth angles during clockwise andanti-clockwise relative rotation.

The dose selector 80 is axially constrained to the housing 10. It isrotationally constrained, via a splined interface 81, 132, to the clutchplate 130. A grip cover 180 is rigidly constrained to the dose selector80.

The torsion spring 90 is attached at one end to the inner housing 190and at the other end to the dial sleeve 60. The torsion spring 90 ispre-wound upon assembly, such that it applies a torque to the dialsleeve 60 when the mechanism is at zero units dialled. The action ofrotating the dose selector 80, to set a dose, rotates the dial sleeve 60relative to the inner housing 190, and winds up the torsion spring 90.

The gauge element 110 is constrained to prevent rotation but allow axialtranslation relative to the housing 10 via a splined interface. It isalso in threaded engagement to the dose indicator 120 such that rotationof the dose indicator 120 causes axial translation of the gauge element110. The design and functions of the gauge window are the same as in thefirst embodiment.

The dose indicator 120 is rotationally constrained, via a splinedinterface, to the dial sleeve 60. They are constrained by the innerhousing 190 to allow rotation but not translation. The dose indicator120 is marked with a sequence of numbers, which are visible through thegauge element 110 and slot 11 in the housing 10, to denote the dialleddose of medicament.

The clutch spring 140 is located between the clutch plate 130 and gripcover 180 and acts to force the clutch plate 130 and driver 40 towardsthe cartridge end of the mechanism. The ratchet teeth 61, 133 (actuallyspline features) are permanently engaged between the dial sleeve 60 andclutch plate 130. The clutch spring 140 biases the clutch plate 130towards the cartridge end to engage splines 132, 81 on the inner surfaceof the dose selector 80. FIG. 14 shows the clutch plate 130 togetherwith the proximal end of the device in more detail.

The bearing 160 is axially constrained to the lead screw 30 and acts onthe bung within the liquid medicament cartridge 170.

The inner housing 190 is a tubular element which is rigidly constrainedto the housing 10 and locks the driver 40 when the trigger 200 is notdepressed by means of toothed interface 41, 191. Near its distal end,there is a clicker arm 192 (FIGS. 15 a, b) interacting with the drivesleeve teeth 41 during dose dispensing to create an audible and/ortactile feedback.

The trigger 200 is constrained to pivot in the housing 10. When thetrigger 200 is depressed, it acts on the trigger inner 210 causing thetrigger inner 210 to translate axially thereby axially translating thedriver 40 and disengaging the driver 40 from its splined toothengagement to the inner housing 190. Actuation of the device by thetrigger results in a low actuation force compared with devices where theuser has to exert the dispensing force.

The trigger inner 210 a ring shaped element which is constrained to moveaxially when the trigger 200 is depressed. The trigger inner 210 has twoprotrusions 211 which extend in the proximal direction (FIG. 15 a). Theprotrusions 211 that act on the driver 40 to disengage the driver 40from the inner housing 190 when the trigger 200 is depressed (FIG. 15b).

The trigger housing 220 clips into the housing 10, and retains thetrigger 200 within its pivot interface with the housing 10.

In the following, the functioning of the disposable drug delivery deviceand its components will be explained in more detail.

The user selects a variable dose of liquid medicament by rotating thedose selector 80 clockwise, which generates an identical rotation in thedial sleeve 60 and hence dose indicator 120. Rotation of the dial sleevecauses charging of the torsion spring 90, increasing the energy storedwithin it. As the dose indicator 120 rotates, the gauge element 110translates axially due to its threaded engagement thereby showing thevalue of the dialled dose. As mentioned above, the gauge element 110 hasflanges 112, 113 either side of the window 111 area which may havevisual differentiation to provide additional feedback to thedialled/delivered dose value. The trigger mechanism also has anergonomic tapered or flattened feature 181 on the Grip Cover 180 whichis functionally part of the dial grip which aids users whilst dialling,especially if they have limited dexterity. The driver 40 is preventedfrom rotating, due to the engagement of its splined teeth 41 with theinner housing 190. Relative rotation must therefore occur between theclutch plate 130 and driver 40 via the ratchet interface 42, 131. Themovement of the nut 50 and cancelling of a set dose is the same asexplained for the first embodiment.

After a dose has been set as explained above for the first embodiment,the device is ready for dose dispensing. Delivery of a dose is initiatedby the user depressing the trigger 200 on the side of the device. FIGS.17 and 18 show the device in the two positions trigger 200 in at restcondition (FIG. 17) and trigger 200 depressed (FIG. 18). When thetrigger 200 is depressed, the trigger acts on the trigger inner 210moving it axially away from the cartridge 170. The trigger inner 210acts on the driver 40 displacing it axially, i.e. the driver 40 movesthe clutch plate 130 axially disengaging the clutch plate 130 from thedose selector 80. Then the drive sleeve spline teeth 41 disengage fromthe corresponding teeth 191 of inner housing 190. The driver 40 can nowrotate and is driven by the torsion spring 90 via the dose indicator120, dial sleeve 60 and clutch plate 130. Rotation of the driver 40causes the lead screw 30 to rotate due to their splined engagement, andthe lead screw 30 then advances due to its threaded engagement to theinner housing 190. During delivery of a dose, the driver 40 and dialsleeve 60 rotate together, so that no relative motion in the nut 50occurs. The nut 50 therefore travels towards its abutment on the driver40 during dialling only.

Delivery of a dose continues via the mechanical interactions describedabove while the user continues to depress the trigger 200. If the userreleases the trigger 200, it returns to its at rest position and thedriver 40 becomes rotationally constrained to the inner housing 190 sothat delivery of a dose is halted.

The dose indicator 120 rotation also causes the gauge element 110 totraverse axially back to its zero position whereby the zero doseabutment 122 stops the mechanism. Once the delivery of a dose isstopped, by the dose indicator 120 returning to the zero dose abutment122, the user may release the trigger 200, which will re-engage theinner housing spline teeth 191 with the drive sleeve teeth 41. Themechanism is now returned to the at rest condition.

Tactile feedback during delivery is provided via the clicker arm 192integrated into the inner housing 190, which interfaces radially withthe spline teeth 41 of the driver 40 when the trigger 200 is depressedand the driver 40 is in its axial dispense position, i.e. in itsproximal position. The spline teeth 41 spacing corresponds to the driver40 rotation required for a single unit dispense. During dispense, as thedriver 40 rotates, the spline features 41 engage with the clicker arm192 to produce an audible click with each dose unit delivered.

It is possible to angle the spline teeth 41, 191 on either one or bothof the driver 40 and inner housing 191 so that when the trigger 200 isreleased the re-engagement of the spline teeth 41, 191 fractionally‘backwinds’ the driver 40 thereby removing the engagement of the doseindicator 120 to the gauge element 110 zero dose stop 122 abutment. Thisremoves the effect of clearances in the mechanism (for example due totolerances) which could otherwise lead to slight advancement of the leadscrew 30 and medicament dispense when the device is dialled for thesubsequent dose (due to the dose indicator 120 zero dose stop 122 nolonger restraining the mechanism and instead the restraint returning tothe splines between the drive sleeve and inner housing 190.

At the end of dose, additional tactile feedback is provided in the formof a “click”, distinctive from the “clicks” provided during dispense, toinform the user that the device has returned to its zero position viathe interaction of three components, namely the dose indicator 120, thegauge element 110 and the trigger inner 210. This embodiment allowsfeedback to only be created at the end of dose delivery and not createdif the device is dialled back to, or away from, the zero position. FIG.16 a shows the position of the features when a dose is dialled. It canbe seen that a semi-flexible arm 123 of the dose indicator 120 does notcontact a flexible arm 114 of the gauge element 110 and therefore duringdialling the flexible arm 114 is not deflected, i.e. it passes over thesemi-flexible arm 123 without interaction of these two arms. During dosedelivery, the trigger 200 forces the trigger inner 210 axially so thattowards the end of dose an arm 212 on the trigger inner 210 forces theflexible arm 114 on the gauge element 110 to deflect axially (FIG. 16b), such that as the mechanism returns to zero the flexible arm 114contacts a protrusion 125 of the semi-flexible arm 123 of the doseindicator 120, creating a “click” as the mechanism reaches the zero stopposition. The arm 114 may have on its radially inner side a protrusionor recess (not shown) for interaction with protrusion 125 onsemi-flexible arm 123.

A third, alternative embodiment is shown in FIGS. 19 and 20. Similar tothe first embodiment, the device of this third embodiment has a dosebutton 70 at its proximal end. The device features a translating doseindicator 120 for activation of the device during dose dispensing. Inother words, the device utilises axial travel of the dose indicator 120during dose button 70 actuation to release the driver 40 from itsrotational lock with the housing 10. This reduces the outer diameter andlength of the mechanism. FIG. 19 shows the device in an at restposition, whereas in FIG. 20 the dose button 70 is depressed. Thefunctions of the components mainly correspond to the first embodiment.

In this third embodiment, the dose button 70 has an axial abutment withthe dose indicator 120. Due to the length of the dose indicator 120, theseparate dial sleeve of the first embodiment is omitted. In its distalregion, the dose indicator 120 acts against a separate locking arm 230which is splined to the housing 10 and has teeth for engagingcorresponding teeth 41 of driver 40. Therefore, as the dose indicator120 moves axially when the dose button 70 is depressed, the locking arm230 is forced to move axially disengaging it from the driver 40 andallowing the torsion spring 90 to deliver the dose. Similarly, when thedose button 70 is released, the dose indicator 120 and locking arm 230return to their original axial position, under the action of the axialspring 240, and the driver 40 is again locked against rotation.

Since the gauge element 110 is threaded to the dose indicator 120, itmoves axially with the dose indicator 120 when the dose button 70 isdepressed and released and therefore the gauge element 110 and Lens orslot 11 of the housing 10 remain aligned to the dose indicator 120 atall times so that the correct dose is displayed.

An additional spring 240 acts on the distal end of dose indicator 120biasing the mechanism in the at rest position, i.e. the proximalposition of the number sleeve. For manufacturing reasons, the driver 40may comprise two rigidly fixed component parts as indicated in FIGS. 19and 20. The nut 50 is located between the driver 40 and the (extended)dose indicator 120.

Although the dose indicator 120 translates axially upon actuation of thedose button 70, there is no axial movement of the dose indicator 120during dose setting nor during dose dispensing.

As can be taken from the above description of the three embodiments,significant features and advantages of the invention include:

The set and/or remaining dose is displayed through a window that movesaxially within the device—the “gauge” feature. This provides additionalvisual dose progress feedback. This feedback can be enhanced if eitherside of this window 111, i.e. flanges 112, 113, has features such asseparate colours and/or markings.

The dose indicator 120 does not translate helically in any embodiment.

The second embodiment has a large user friendly dose selector 80 profilewith grip cover 180 to aid dose setting. This is only feasible if thereis no button on the end.

The end button mechanisms of the first and third embodiments have anoversized dose selector 80 to aid dose setting.

An end-of-dose click is incorporated in each mechanism that operatesduring dose delivery but not dose setting or cancellation.

An alternative third embodiment exists for the end button mechanism ofthe first embodiment whereby the dose indicator 120 moves axially duringdose button 70 actuation and release, but not during dose delivery.

An alternative fourth embodiment of an injection device 1 is shown inFIG. 21 in an exploded view. The injection device comprises 19components, excluding the liquid medicament cartridge. In more detail,the device comprises a housing 410, which includes a main housing 411, aproximal cap 412 and a cartridge holder 413, a dial grip 420, a dispensebutton 430, a dial tube 440, a last dose nut 450, a sleeve-like clicker460, a dispense spring 470, a dose indicator (dial sleeve) 480, asliding gauge 490, a drive member 500 including a drive sleeve 501 and adrive tube 502, a motor spring 510, a storage spool 520, a piston rod(lead screw) 530 with a bearing 531, a lens (not shown) and a cap (notshown). Most of the components are located concentrically about one oftwo principle axes I and II of the mechanism as shown in FIG. 22.

The piston rod 530 is located within the housing 510. The drive member500 is permanently coupled to the piston rod 530 and the drive member500 is axially movable between a dose setting position, in which thedrive member 500 is rotationally constrained to the housing 410, and adose dispensing position, in which the drive member 500 is rotationallyde-coupled from the housing 410. The power reservoir 510 for driving thedrive member 500 comprising a reverse wound flat spiral spring as apower reservoir having a first end attached to the first spool 520 and asecond end attached to a second spool, which is axially and rotationallyconstrained to drive member 500. For example, the second spool is anintegral part of drive sleeve 501. In the embodiment shown in theFigures, the second end of the spring 510 comprises a portion of reducedwidth and a free end portion having an increased width compared with theportion of reduced width, wherein the drive member 500, in more detaildrive sleeve 501, comprises a cylindrical spool portion having an axialslot 503 and an adjacent narrow recess.

Preferably, the dose indicator 480 is axially constrained to the housing410 and rotates during dose setting relative to the housing in either afirst direction (increasing a dose) or a second opposite direction(decreasing a dose) and it rotates during dose dispensing relative tothe housing in the second opposite direction. The gauge element 490 isat least partly interposed between the housing 410 and the doseindicator 480 and at least partly visible through at least one apertureor window of the housing 410. Further, the gauge element 490 is axiallyguided within the housing 410 and in threaded engagement with the doseindicator 480 such that rotation of the dose indicator 480 causes anaxial displacement of the gauge element 490. The housing 410 has anaperture or window and the gauge element 490 has a further aperture orwindow, which is positioned with respect to the aperture or window ofthe housing such that at least a part of the dose indicator 480 isvisible through the apertures or windows.

In particular, the apertures may be located on the main housing 411 in alocation which is visible to the user during dispense of a dose. Thismay be close to the distal end of the device. Particularly this may be alocation in which the number display of the dose indicator 480 could notfeasibly be located. There may also be a plurality of gauge apertures.In particular there may be two gauge apertures, located on oppositesides of the device This increases the visibility of the analog gaugefeature for users with a preference for left handed operation, or thoseusers with a preference to hold the device with an alternative grip. Theanalog gauge is particularly beneficial as an indicator of the doseposition of the device during dispense of a dose. During dispense of adose the number digit display may be changing too quickly for individualdose position markings to be legible. It may therefore be difficult forthe user to understand the rate at which the dose is being dispensed,and the amount of medicament still to be dispensed. The axial motion ofthe analog gauge, which increasingly covers a further surface as a doseis dispensed, gives a simple visible indicator of the dispense rate andthe amount of medicament still be to dispensed during the dispenseevent.

The injection device comprises a limiter mechanism defining a maximumsettable dose and a minimum settable dose. The limiter mechanism maycomprise a first rotational stop on the dose indicator 480 and a firstcounter stop on the gauge element 490, which abut in the minimum dose(zero) position, and a second rotational stop on the dose indicator 480and a second counter stop on the gauge element 490, which abut in themaximum dose position.

The dispense button 430 is axially displaceable and located surroundedby the dial grip 420 which is axially constrained to the housing 410.The clicker sleeve 460 is rotationally constrained to the housing 410and is axially displaceable relative to the housing between a proximaldose setting position and a distal dose dispensing position. Further,the clicker sleeve 460 comprises teeth releasably engaging correspondingteeth of the dial sleeve 440 which is rotatable during dose setting. Thedose indicator 480 may comprise a flexible clicker arm, which isdisplaceable by the clicker sleeve 460 in a first direction and onlyduring dose dispensing when the device reaches its minimum dose (zero)position in a second, opposite direction by a protruding section of thegauge element 490.

The injection device may further comprise a last dose protectionmechanism for preventing the setting of a dose, which exceeds the amountof liquid left in a cartridge. This last dose protection mechanismcomprises the nut member 450 located interposed between the clickersleeve 460 and the dial sleeve 440.

In the injection device the first spool 520 is located concentricallywith the piston rod 530 on the first longitudinal axis I, and the secondspool, i.e. the drive sleeve 501, is located on a second longitudinalaxis II, wherein the first longitudinal axis I is parallel to and spacedfrom the second longitudinal axis II. As mentioned above, the drivemember 500 may comprise the drive tube 502 which is rotatable about thefirst longitudinal axis I and the drive sleeve 501 which is rotatableabout the second longitudinal axis II. The drive sleeve 501 is axiallymovable between the dose setting position, in which the drive sleeve 501is rotationally constrained to the housing 410, and the dose dispensingposition, in which the drive sleeve 501 is rotationally de-coupled fromthe housing 410. The drive tube 502 may be permanently rotationallycoupled to the drive sleeve 501 or at least if the drive sleeve 501 isin its dose dispensing position.

A clutch 483, 505 is provided interposed between the dose indicator 480and the drive member 500, wherein the clutch 483, 505 allows relativerotational movement between the dose indicator 480 and the drive member500 during dose setting and prevents relative rotational movementbetween the dose indicator 480 and the drive member 500 during dosedispensing. As shown in FIG. 21, the clutch comprises a ring of teeth505 on the distal side of drive sleeve 501 and inner splines 483 on thedose indicator. The drive sleeve 501 further has a ring of teeth 506 atits proximal end which mesh with corresponding teeth on the drive tube502. In addition, teeth 506 couple the drive sleeve 501 rotationally tothe housing in the (proximal) dose setting position of the drive sleeve501.

Each of the above features is independent from the other features andindependent from the internal functions of the other component parts,like the clutch, the ratchets, the clickers, the dose display or theactuation means.

A further common feature of all embodiments is that the device has nodial extension, i.e. the length of the device is the same whether a dosehas been dialled or not. In addition, the dose selector 80 does not spinduring dispense and it is shaped (either flattened or large diameter) tomake dialling easier. The gauge element 110 provides qualitativefeedback to the user on the progress of the dose. This is especiallyimportant for visually impaired users who may find it difficult toidentify individual numbers or symbols on the number sleeve. All ofwhich should provide a significant ergonomic benefit to the user.

1. An injection device comprising a housing (10;410), a dose settingmember (80, 60; 420, 440) operatively connected to a dose indicator(120; 480) positioned within the housing (10, 410), the dose settingmember (80, 60; 420, 440) and the dose indicator (120; 480) cooperatingto set the dose to be ejected from the injection device, wherein thedose indicator (120; 480), during dose setting, is adapted to undergo amere rotational movement, preferably for more than 360°, within thehousing (10; 410) and relative to the housing (10; 410), characterizedin that the device further comprises a resilient member (90; 510)adapted to provide a force necessary for ejecting a dose from theinjection device.
 2. The injection device according to claim 1, furthercomprising a piston rod (30; 530) having a threaded outer surface withat least one drive track (32) arranged in a longitudinal direction ofthe outer surface of the piston rod (30; 530), a drive member (40; 500)engaging at least part of the drive track (32) of the piston rod (30;530) and being releasably coupled to the dose indicator (120; 480), thedrive member (40) being adapted to drive and rotate with the piston rod(30; 530) during ejection of a dose from the injection device whereinthe housing (10; 410) has a threaded portion (12) cooperating with thethreaded outer surface (31) of the piston rod (30; 530) so that rotationof the piston rod (30; 530) results in an axial movement of the pistonrod (30; 530).
 3. The injection device according to claim 1 or 2,further comprising a gauge element (110; 490) which is rotationallyconstrained to the housing (10; 410) and axially displaceable relativeto the housing (10; 410).
 4. The injection device according to claim 3,wherein the gauge element (110; 490) is in threaded engagement with thedose indicator (120; 480) such that rotation of the dose indicatorcauses an axial displacement of the gauge element (110; 490) relative tothe dose indicator (120; 480) and relative to the housing (10; 410). 5.The injection device according to claim 3 or 4, wherein the doseindicator (120; 480) is marked with a sequence of numbers or symbols,wherein the gauge element (110; 490) comprises an aperture or window(111), and wherein the dose indicator (120; 480) is located radiallyinwards of the gauge element (110; 490), such that at least one of thenumbers or symbols on the dose indicator (120; 480) is visible throughthe aperture or window (111).
 6. The injection device according to anyof the preceding claims, wherein the resilient member (90) is a torsionspring which is strained during dose setting.
 7. The injection deviceaccording to any of the preceding claims, comprising a limiter mechanism(122, 110) defining a maximum settable dose and a minimum settable dose.8. The injection device according to claims 3 to 5 and 7, wherein thelimiter mechanism comprises a first rotational stop (122) on the doseindicator (120) and a first counter stop on the gauge element (110),which abut in the minimum dose (zero) position, and a second rotationalstop on the dose indicator (120) and a second counter stop on the gaugeelement (110), which abut in the maximum dose position.
 9. The injectiondevice according to any of the preceding claims, comprising a last doseprotection mechanism (40, 50, 60; 120; 440, 450, 460) for preventing thesetting of a dose, which exceeds the amount of liquid left in acartridge (170).
 10. The injection device according to claims 2 to 9,wherein the last dose protection mechanism comprises a nut member (50;450) located interposed between the drive member (40) and a component(60; 120; 440) which rotates during dose setting and dose dispensing.11. The injection device according to claim 10, wherein the component(60; 120) which rotates during dose setting and dose dispensing is thedose indicator (120) or a dial sleeve (60) rotationally constrained tothe dose indicator (120).
 12. The injection device according to any ofthe preceding claims, further comprising a clutch (130; 483, 505)arranged between the drive member (40; 500) and the dose indicator (120;480), wherein the clutch allows relative rotation of the drive member(40; 500) and the dose indicator (120; 480) during dose setting androtationally constrains the drive member (40; 500) and the doseindicator (120; 480) during dose dispensing.
 13. The injection deviceaccording to any of the preceding claims, further comprising at leastone first clicker (42, 131; 41, 13; 41, 192) producing an audible and/ortactile first feedback during dose setting and/or dose dispensing and asecond clicker (114, 123) producing an audible and/or tactile secondfeedback, distinct from the first feedback, during dose dispensing whenthe device reaches its minimum dose (zero) position.
 14. The injectiondevice according to any of the preceding claims comprising an actuatingelement (70; 200; 430) for releasing the resilient member (90; 510)which actuating element either comprises a button (70; 430) located onthe proximal end of the housing (10; 410) or a trigger (200) located ona lateral side of the housing (10; 410).
 15. The injection deviceaccording to any of the preceding claims further comprising a cartridge(170) containing a medicament.